Developing and validating a prediction model of live birth following single vitrified-warmed blastocyst transfer.

RESEARCH QUESTION: Can the developed clinical prediction model offer an accurate estimate of the likelihood of live birth, involving blastocyst morphology and vitrification day after single vitrified-warmed blastocyst transfer (SVBT), and therefore assist clinicians and patients? STUDY DESIGN: Retrospective cohort study conducted at a Spanish university-based reproductive medicine unit (2017-2021) including consecutive vitrified-warmed blastocysts from IVF cycles. A multivariable logistic regression incorporated key live birth predictors: vitrification day, embryo score, embryo ploidy status and clinically relevant variables, i.e. maternal age. RESULTS: The training set involved 1653 SVBT cycles carried out between 2017 and 2020; 592 SVBT cycles from 2021 constituted the external validation dataset. The model revealed that female age and embryo characteristics, including overall quality and blastulation day, is linked to live birth rate in SVBT cycles. Stratification by vitrification day and quality (from day-5A to day-6 C blastocysts) applied to genetically tested and untested embryos. The model's area under the curve was 0.66 (95% CI 0.64 to 0.69) during development and 0.65 (95% CI 0.61 to 0.70) in validation, denoting moderate discrimination. Calibration plots showed strong agreement between predicted and observed probabilities. CONCLUSION: By incorporating essential predictors such as vitrification day, embryo morphology grade, age and preimplantation genetic testing for aneuploidy usage, this predictive model offers valuable guidance to clinicians and patients, enabling accurate forecasts of live birth rates for any given vitrified blastocyst within SVBT cycles. Additionally, it serves as a potentially indispensable laboratory tool, aiding in selecting the most promising blastocysts for optimal outcomes.

Endometrial receptivity in women with endometriosis.

As endometriosis is recognized as a contributing factor to infertility, prompting couples to embark on Assisted Reproductive Technology (ART) treatments, it becomes crucial to comprehend the extent and way this condition can affect success rates. Natural conception data reveal lower success rates for women with endometriosis, yet the same cannot be extrapolated to the outcomes of in vitro fertilization (IVF). In recent years, advancements in the ART process, particularly the distinct stages of the IVF pathway and investigations into embryo quality have shown a comparable rate of embryonic quality and chromosomal normalcy (euploidy) between embryos obtained from individuals with or without endometriosis. Thus, the primary question that lingers relates to the functionality of the endometrium. This review addresses whether endometriosis can influence endometrial receptivity and implantation rates.

Progesterone levels during ovarian stimulation in segmented ART cycles inversely correlate with normalized birthweight of neonates conceived through subsequent frozen-thawed embryo transfer.

PURPOSE: To evaluate the association between serum progesterone (P) at the day of ovulation trigger and neonatal birthweight in singletons born after frozen-thawed embryo transfer in segmented ART cycles. METHODS: A retrospective multicenter cohort study involving data from patients who achieved uncomplicated pregnancy and term delivery of ART-conceived singleton babies following a segmented GnRH antagonist cycle. The main outcome was birthweight's z-score of the neonate. Univariate and multivariate linear logistic regression analyses were made to investigate the relation of z-score with variables inherent to the patient and to the ovarian stimulation. The variable P per oocyte was created by dividing the value of progesterone at ovulation trigger by the number of oocytes retrieved at oocyte retrieval. RESULTS: A total of 368 patients were included in the analysis. At univariate linear regression, the birthweight z-score of the neonate appeared to be inversely related to both P levels at the ovulation trigger (- 0.101, p = 0.015) and P levels per oocyte at trigger (- 1.417, p = 0.001), while it was directly related to the height of the mother (0.026, p = 0.002) and to the number of previous live births (0.291, p = 0.016). In multivariate analysis, both serum P (- 0.1; p = 0.015) and P per oocyte (- 1.347, p = 0.002) maintained the significant inverse association with birthweight z-score after adjusting for height and parity. CONCLUSIONS: Serum progesterone level on the day of ovulation trigger inversely correlates with normalized birthweight of neonates in segmented GnRH antagonist ART cycles.

Clinical pregnancy rate for frozen embryo transfer with HRT: a randomized controlled pilot study comparing 1 week versus 2 weeks of oestradiol priming.

RESEARCH QUESTION: Does a frozen-embryo transfer in an artificially-prepared endometrium (FET-HRT) cycle yield similar clinical pregnancy rate with 7 days of oestrogen priming compared to 14 days? DESIGN: This is a single-centre, randomized, controlled, open-label pilot study. All FET-HRT cycles were performed in a tertiary centre between October 2018 and January 2021. Overall, 160 patients were randomized, with a 1:1 allocation, into two groups of 80 patients each: group A (7 days of E2 prior to P4 supplementation) and group B (14 days of E2 prior to P4 supplementation). Both groups received single blastocyst stage embryos on the 6th day of vaginal P4 administration. The primary outcome was the feasibility of such strategy assessed as clinical pregnancy rate, secondary outcomes were biochemical pregnancy rate, miscarriage rate, live birth rate and serum hormone levels on the day of FET. Chemical pregnancy was assessed by an hCG blood test 12 days after FET and clinical pregnancy was confirmed by transvaginal ultrasound at 7 weeks. RESULTS: The analysis included 160 patients who were randomly assigned to either group A or group B on the seventh day of their FET-HRT cycle if the measured endometrial thickness was above 6.5 mm. Following screening failures and of drop-outs, 144 patients were finally included both in group A (75 patients) or group B (69 patients). Demographic characteristics for both groups were comparable. The biochemical pregnancy rate was 42.5% and 48.8% for group A and group B, respectively (p 0.526). Regarding the clinical pregnancy rate at 7 weeks, no statistical difference was observed (36.3% vs 46.3% for group A and group B, respectively, p = 0.261). The secondary outcomes of the study (biochemical pregnancy, miscarriage, and live birth rate) were comparable between the two groups for IIT analysis, as well as the P4 values on the day of FET. CONCLUSIONS: In a frozen embryo transfer cycle, performed with artificial preparation of the endometrium, 7 versus 14 days of oestrogen priming are comparable, in terms of clinical pregnancy rate; the advantages of a seven-day protocol include the shorter time to pregnancy, reduced exposure to oestrogens, and more flexibility of scheduling and programming, and less probability to recruit a follicle and have a spontaneous LH surge. It is important to keep in mind that this study was designed as a pilot trial with a limited study population as such it was underpowered to determine the superiority of an intervention over another; larger-scale RCTs are warranted to confirm our preliminary results. TRIAL REGISTRATION: Clinical trial number: NCT03930706.

Elevated serum progesterone levels before frozen embryo transfer do not negatively impact reproductive outcomes: a large retrospective cohort study.

OBJECTIVE: To evaluate whether patients with high-serum progesterone levels before frozen embryo transfer (FET) under hormonal replacement therapy present with worse reproductive outcomes. DESIGN: A cohort retrospective study. SETTING: A university-affiliated fertility center. PATIENT(S): A total of 3,183 FET cycles in patients receiving hormonal replacement therapy between March 2009 and December 2020 were included. The luteal phase was covered with 200 mg per 8 hours of vaginal micronized progesterone either alone or in combination with a daily subcutaneous injection of 25 mg of progesterone. A total of 1,360 cycles corresponded to frozen homologous embryo transfer (ET) (hom-FET), 1,024 were euploid ET (eu-FET) after preimplantation genetic testing for aneuploidies, and 799 cycles were frozen heterologous ET (het-FET). All patients had adequate serum progesterone levels (≥10.6 ng/mL) before the procedure. INTERVENTION(S): Frozen embryo transfer cycles. MAIN OUTCOME MEASURE(S): Clinical pregnancy, miscarriage, and live birth rates (LBRs). RESULTS: Median (P25; P75) serum progesterone level before FET was 14.39 (12.43-17.49) ng/mL. Progesterone levels were significantly higher in the group under vaginal plus subcutaneous progesterone (15.96 [13.74-21.60] vs. 14.09 [12.19-16.95]). No differences in clinical pregnancy, miscarriage, and LBR were observed based on the use of vaginal or vaginal plus subcutaneous progesterone for each of the groups (hom-FET, eu-FET, and het-FET). Live birth rates were comparable among patients in the highest centile of serum progesterone levels (≥p90) (22.33 ng/mL) and the rest of the patients (p<90) (43.9% vs. 41.3%). Patients with progesterone levels ≥p90 presented lower body mass index than those in the lower centiles (

Prenatal screening after preimplantation genetic testing for aneuploidy: time to evaluate old strategies.

RESEARCH QUESTION: How does first-trimester aneuploidy screening perform in pregnancies achieved through IVF with preimplantation genetic testing for aneuploidy (PGT-A) in a medical setting? DESIGN: This retrospective cohort study was undertaken in a single tertiary care centre between January 2013 and June 2022. In total, 20,237 women had prenatal follow-up at the study centre and were included in the study. The women were divided into three groups: singleton pregnancies conceived through the transfer of a PGT-A-screened euploid embryo (n = 510); singleton pregnancies conceived through IVF without PGT-A (n = 3291); and singleton pregnancies conceived naturally (n = 16,436). RESULTS: The conventional combined screening test for pregnancies conceived through IVF with PGT-A had specificity of 91%; sensitivity could not be calculated as there were no cases of fetal aneuploidy in this group. In 89.1% of pregnancies conceived through IVF with PGT-A with high risk for trisomy 21, 18 or 13, the result was related to advanced maternal age (>35 years at time of screening). CONCLUSIONS: The current screening strategy for trisomies 21, 18 and 13 can generate unnecessary tests in pregnancies achieved through IVF with PGT-A. A new protocol is needed for these patients, with greater weight given to ultrasound markers.

Blastocyst versus cleavage embryo transfer improves cumulative live birth rates, time and cost in oocyte recipients: a randomized controlled trial.

RESEARCH QUESTION: Does embryo transfer day (day 5 versus day 3) affect cumulative live birth rates (CLBR), time to live birth (TLB) and cost per live birth (CPL) in recipients of donated oocytes? STUDY DESIGN: A single-centre RCT conducted between April 2017 and August 2018. Recipients of donated oocytes were randomized to cleavage-stage (day 3) or to blastocyst-stage (day 5) embryo transfer. Eligible recipients were aged 18-50 years and in their first or second synchronous cycle. Primary outcome was CLBR (12 months from first embryo transfer), and fresh and subsequent cryopreserved transfers were considered; TLB and CPL were also analysed. RESULTS: Recipients (n = 134) were randomized to the day-3 group (n = 69) or to the day-5 group (n = 65). Day-5 transfer resulted in a 15.9% relative increase in CLBR and a significant shorter TLB compared with day-3 transfer. To reach a 50% CLBR, the day-3 group required 6 months more than the day-5 group (15.3 versus 8.9 months, respectively). The average CPL in the day-3 strategy cost 24% more than the day-5 strategy (€14817.10 versus €10959.20). Clinical pregnancy rate was 25% less in the day-3 group. The trial was prematurely stopped after poor initial results in the day-3 arm led to unplanned interim analysis. CONCLUSIONS: The transfer of blastocyst-stage embryos in recipients of donated oocytes is preferred as it leads to a higher clinical pregnancy rate, live birth rate, shorter time to pregnancy and lower costs to achieve live birth, compared with cleavage-stage embryo transfer.

Artificially prepared vitrified-warmed embryo transfer cycles are associated with an increased risk of pre-eclampsia.

RESEARCH QUESTION: What is the association between the development of pre-eclampsia and endometrial preparation prior to vitrified-warmed embryo transfer (frozen embryo transfer, FET)? DESIGN: A retrospective cohort study at a tertiary university-based hospital, including a total of 536 pregnant patients who underwent a FET between 2010 and 2019 and delivered in the same institution; 325 patients underwent natural cycle FET (NC-FET) and 211 artificial cycle FET (AC-FET). RESULTS: Unadjusted, the incidence of pre-eclampsia was significantly higher in AC-FET cycles than in NC-FET cycles (3.7% versus 11.8%, P < 0.001). Multivariable logistic regression analysis showed that, when adjusting for type of endometrial preparation (artificial cycle versus natural cycle), oocyte recipient cycles and African ethnicity, the risk of developing pre-eclampsia was significantly associated with artificial endometrial preparation or oocyte recipient cycles (AC-FET versus NC-FET: odds ratio 2.9, 95% confidence interval 1.4-6.0, P = 0.005). CONCLUSIONS: The current data show a higher incidence of pre-eclampsia in AC-FET versus NC-FET cycles, adding further strength to the existing data on this topic. Together, these recent findings may result in a change in clinical practice, towards a preference for NC-FET cycles over AC-FET cycles in ovulatory patients. Screening for high-risk patients and the development of strategies to mitigate their risk profile could reduce the risk of pre-eclampsia. Further understanding of the different vasoactive substances excreted by the corpus luteum is vital.

Progesterone-primed ovarian stimulation in oocyte donation: a model for elective fertility preservation?

RESEARCH QUESTION: Does type of LH peak suppression (progesterone-primed ovarian stimulation [PPOS] versus gonadotrophin releasing hormone [GnRH] antagonist) affect oocyte competence, embryo development and live birth rates in recipients of vitrified donated oocytes? DESIGN: Retrospective cohort study conducted between 2016 and 2018, involving 187 recipient cycles of donated vitrified oocytes. Oocyte donors were stimulated under LH suppression with desogestrel for PPOS (DSG group) or ganirelix GnRH antagonist (ANT group). Recipients younger than 50 years received vitrified oocytes from DSG donation cycles (DSG-R) or ANT donation cycles (ANT-R). RESULTS: A mean of 10.07 ± 3.54 oocytes per recipient were warmed (survival rate of 80.7%), and 5.90 ± 2.89 were fertilized (fertilization rate 72.6%). Out of 187 recipients, 168 achieved embryo transfers. No significant differences were found in warming survival rates, fertilization rates and embryo development between DSG-R and ANT-R groups. Ninety-four clinical pregnancies and 81 live births were achieved. No statistically significant differences were found in clinical pregnancy rates (47.7% versus 52.5, P = 0.513) and live birth rates (39.5% versus 46.5%, P = 0.336) per recipient cycle between DSG-R and ANT-R, respectively. Multivariable logistic regression was applied to assess the effect of treating oocyte donors. Live birth rate adjusted for associated factors was not statistically different between vitrified oocytes from DSG or ANT (OR 0.74, 95% CI 0.37 to 1.47). CONCLUSION: Reproductive outcomes of recipients of vitrified oocytes are not affected by donor PPOS treatment. PPOS is suitable for suppressing LH peak in elective fertility preservation and in freeze-all strategies.

Type and dose of gonadotropins in poor ovarian responders: does it matter?

Infertile patients with a diminished ovarian reserve, also referred to as poor ovarian responders, constitute a substantial and increasing population of patients undergoing in vitro fertilization. The management of patients with poor ovarian response is still a controversial issue. Almost a century has passed since the introduction of the first gonadotropin. A broad collection of urinary and recombinant gonadotropins, including biosimilars, is commercially available now. Despite great advances in assisted reproductive technology, there remains uncertainty about the optimal treatment regimen for ovarian stimulation in poor ovarian responders. Although oocyte donation is the most successful and ultimate remedy for poor ovarian responders, most patients persist on using their own oocytes in several attempts, to achieve the desired pregnancy. The aim of this review is twofold: first, to provide an overview of the commercially available gonadotropins and summarize the available evidence supporting the use of one or another for ovarian stimulation in poor ovarian responders, and second, to address the controversies on the dosage of gonadotropins for this specific in vitro fertilization population.

Ovarian stimulation for oocyte donation: a systematic review and meta-analysis.

BACKGROUND: Since its introduction in the 1980s, oocyte donation (OD) has been largely integrated into ART. Lately, both demand and the indications for OD have increased greatly. Oocyte donors are healthy and potentially fertile women undergoing voluntarily ovarian stimulation (OS). Selection of the optimal type of stimulation is of paramount importance in order to achieve the most favourable outcomes for the oocyte recipients, but most importantly for the safety of the oocyte donors. OBJECTIVE AND RATIONALE: This is the first systematic review (SR) with the objective to summarize the current evidence on OS in oocyte donors. The scope of this SR was to evaluate the OD programme by assessing four different aspects: how to assess the ovarian response prior to stimulation; how to plan the OS (gonadotrophins; LH suppression; ovulation trigger; when to start OS); how to control for the risk of ovarian hyperstimulation syndrome (OHSS) and other complications; and the differences between the use of fresh versus vitrified donated oocytes. SEARCH METHODS: A systematic literature search was conducted in May 2020, according to PRISMA guidelines in the databases PubMed and Embase, using a string that combined synonyms for oocytes, donation, banking, freezing, complications and reproductive outcomes. Studies reporting on the safety and/or efficacy of OS in oocyte donors were identified. The quality of the included studies was assessed using ROBINS-I and ROB2. Meta-analysis was performed where appropriate. Data were combined to calculate mean differences (MD) for continuous variables and odd ratios (OR) for binary data with their corresponding 95% CIs. Heterogeneity between the included studies was assessed using I2 and tau statistics. OUTCOMES: In total, 57 manuscripts were selected for the review, out of 191 citations identified. Antral follicle count and anti-Müllerian hormone levels correlate with ovarian response to OS in OD but have limited value to discriminate donors who are likely to show either impaired or excessive response. Five randomized controlled trials compared different type of gonadotrophins as part of OS in oocyte donors; owing to high heterogeneity, meta-analysis was precluded. When comparing different types of LH control, namely GnRH antagonist versus agonist, the studies showed no differences in ovarian response. Use of progesterone primed ovarian stimulation protocols has been evaluated in seven studies: the evidence has shown little or no difference, compared to GnRH antagonist protocols, in mean number of retrieved oocytes (MD 0.23, [95% CI 0.58-1.05], n = 2147; 6 studies; I2 = 13%, P = 0.33) and in clinical pregnancy rates among recipients (OR 0.87 [95% CI 0.60-1.26], n = 2260, I2 = 72%, P < 0.01). There is insufficient evidence on long-term safety for babies born. GnRH agonist triggering is the gold standard and should be used in all oocyte donors, given the excellent oocyte retrieval rates, the practical elimination of OHSS and no differences in pregnancy rates in recipients (four studies, OR 0.86, 95%CI 0.58-1.26; I2 = 0%). OS in OD is a safe procedure with a low rate of hospitalization after oocyte retrieval. The use of a levonorgestrel intrauterine device or a progestin contraceptive pill during OS does not impact the number of oocytes retrieved or the clinical pregnancy rate in recipients. Ultrasound monitoring seems enough for an adequate follow up of the stimulation cycle in OD. Use of fresh versus vitrified donated oocytes yielded similar pregnancy outcomes. WIDER IMPLICATIONS: This update will be helpful in the clinical management of OS in OD based on the most recent knowledge and recommendations, and possibly in the management of women under 35 years undergoing oocyte vitrification for social freezing, owing to the population similarities. More clinical research is needed on OS protocols that are specifically designed for OD, especially in term of the long-term safety for newborns, effective contraception during OS, and treatment satisfaction.

Fertility in patients with untreated rectosigmoid endometriosis.

RESEARCH QUESTION: Several studies have investigated reproductive outcomes following surgical treatment of colorectal endometriosis, mainly segmental colorectal resection. This study examines pregnancy and live birth rates of women with rectosigmoid endometriosis not treated by surgery. DESIGN: A retrospective analysis of data collected between May 2009 and January 2020 related to 215 women affected by rectosigmoid endometriosis wishing to conceive. Patients had a diagnosis of rectosigmoid endometriosis by transvaginal ultrasonography and magnetic resonance imaging enema. Patients with estimated bowel stenosis >70% at computed tomographic colonography and/or subocclusive/occlusive symptoms were excluded. RESULTS: During the median length of follow-up of 31 months (range 13-63 months), the total pregnancy and live birth rates of the study population were 47.9% and 45.1%, respectively. Sixty-two women had a live birth after natural conception (28.8%; 95% confidence interval [CI] 22.8-35.6%) with a median time required to conceive of 10 months (range 2-34 months). Eighty-three women underwent infertility treatments (38.6%, 95% CI 32.1-45.5%); among these, 68 patients underwent IVF either directly (n = 51) or after intrauterine insemination (IUI) failure (n = 17). Time to conception was significantly higher in women having conceived by IVF than in those having conceived naturally (P < 0.001) or by IUI (P = 0.006). In patients undergoing IVF cycles, a worsening of some pain and intestinal symptoms was observed. CONCLUSIONS: At median follow-up of 31 months, women with rectosigmoid endometriosis have a 48% pregnancy rate. However, these patients must be referred to centres specialized in managing endometriosis to properly assess symptoms and degree of bowel stenosis.

Luteal Phase Support in IVF: Comparison Between Evidence-Based Medicine and Real-Life Practices.

Background: Luteal phase support (LPS) in assisted reproduction cycles has been widely investigated in recent years. Although progesterone represents the preferential product for luteal phase supplementation in cycles with fresh embryo transfer, there is ongoing debate as to when to start, which is the best route, dosage and duration, and whether there is a place for additional agents. Nevertheless, fertility specialists do not always adhere to evidence-based recommendations in their clinical practice. The aim of this worldwide web-based survey is to document the currently used protocols for luteal phase support and appraisal tendencies of drug prescription behavior and to compare these to the existing evidence-based literature. Material and Methods: A questionnaire was developed and sent by secure e-mail to 1,480 clinicians involved in ART worldwide. One hundred and forty-eighth clinicians from 34 countries returned completed questionnaires. Results: Progesterone support is usually started on the day of oocyte retrieval. Eighty percent of clinicians applied the administration of vaginal progesterone only. Intramuscular progesterone was prescribed by 6%, while oral progestin or subcutaneous progesterone were each prescribed by 5% of clinicians, respectively. Progesterone was administered until 8-10 weeks' gestation by 35% and 12 weeks by 52% of respondents. Conclusions: Vaginal administration was the preferred route for luteal phase support. The reported emerging use of the oral route confirms the expected shift in clinical practice as a result of recent evidence showing a reassuring safety score of oral progestins. In spite of the lack of evidence supporting the continuation of luteal support until 12 weeks' gestation, this practice was adhered to by more than half of the clinicians surveyed, highlighting the difference between evidence-based medicine and real-life practices.

The freeze-all strategy versus agonist triggering with low-dose hCG for luteal phase support in IVF/ICSI for high responders: a randomized controlled trial.

STUDY QUESTION: Does the freeze-all strategy in high-responders increase pregnancy rates and improve safety outcomes when compared with GnRH agonist triggering followed by low-dose hCG intensified luteal support with a fresh embryo transfer? SUMMARY ANSWER: Pregnancy rates after either fresh embryo transfer with intensified luteal phase support using low-dose hCG or the freeze-all strategy did not vary significantly; however, moderate-to-severe ovarian hyperstimulation syndrome (OHSS) occurred more frequently in the women who attempted a fresh embryo transfer. WHAT IS KNOWN ALREADY: Two strategies following GnRH agonist triggering (the freeze-all approach and a fresh embryo transfer attempt using a low-dose of hCG for intensified luteal phase support) are safer alternatives when compared with conventional hCG triggering with similar pregnancy outcomes. However, these two strategies have never been compared head-to-head in an unrestricted predicted hyper-responder population. STUDY DESIGN, SIZE, DURATION: This study included women with an excessive response to ovarian stimulation (≥18 follicles measuring ≥11 mm) undergoing IVF/ICSI in a GnRH antagonist suppressed cycle between 2014 and 2017. Our primary outcome was clinical pregnancy at 7 weeks after the first embryo transfer. Secondary outcomes included live birth and the development of moderate-to-severe OHSS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Following GnRH agonist triggering, women were randomized either to cryopreserve all good-quality embryos followed by a frozen embryo transfer in an subsequent artificial cycle or to perform a fresh embryo transfer with intensified luteal phase support (1500 IU hCG on the day of oocyte retrieval, plus oral estradiol 2 mg two times a day, plus 200 mg of micronized vaginal progesterone three times a day). MAIN RESULTS AND THE ROLE OF CHANCE: A total of 212 patients (106 in each arm) were recruited in the study, with three patients (one in the fresh embryo transfer group and two in the freeze-all group) later withdrawing their consent to participate in the study. One patient in the freeze-all group became pregnant naturally (clinical pregnancy diagnosed 38 days after randomization) prior to the first frozen embryo transfer. The study arms did not vary significantly in terms of the number of oocytes retrieved and embryos produced/transferred. The intention to treat clinical pregnancy and live birth rates (with the latter excluding four cases lost to follow-up: one in the fresh transfer and three in the freeze-all arms, respectively) after the first embryo transfer did not vary significantly among the fresh embryo transfer and freeze-all study arms: 51/105 (48.6%) versus 57/104 (54.8%) and 41/104 (39.4%) versus 42/101 (41.6%), respectively (relative risk for clinical pregnancy 1.13, 95% CI 0.87-1.47; P = 0.41). However, moderate-to-severe OHSS occurred solely in the group that received low-dose hCG (9/105, 8.6%, 95% CI 3.2% to 13.9% vs 0/104, 95% CI 0 to 3.7, P < 0.01). LIMITATIONS, REASONS FOR CAUTION: The sample size calculation was based on a 19% absolute difference in terms of clinical pregnancy rates, therefore smaller differences, as observed in the trial, cannot be reliably excluded as non-significant. WIDER IMPLICATIONS OF THE FINDINGS: This study offers the first comparative analysis of two common strategies applied to women performing IVF/ICSI with a high risk to develop OHSS. While pregnancy rates did not vary significantly, a fresh embryo transfer with intensified luteal phase support may still not avoid the risk of moderate-to-severe OHSS and serious consideration should be made before recommending it as a routine first-line treatment. Future trials may allow us to confirm these findings. STUDY FUNDING/COMPETING INTEREST(S): The authors have no conflicts of interest to disclose. No external funding was obtained for this study. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT02148393. TRIAL REGISTRATION DATE: 28 May 2014. DATE OF FIRST PATIENT'S ENROLMENT: 30 May 2014.

Is ovarian response associated with adverse perinatal outcomes in GnRH antagonist IVF/ICSI cycles?

RESEARCH QUESTION: Is there an association between ovarian response and perinatal outcomes? DESIGN: A retrospective, single-centre cohort study including all women undergoing their first ovarian stimulation cycle in a gonadotrophin releasing hormone antagonist protocol, with a fresh embryo transfer that resulted in a singleton live birth from January 2009 to December 2015. Patients were categorized into four groups according to the number of oocytes retrieved: one to three (category 1), four to nine (category 2), 10-15 (category 3), or over 15 oocytes (category 4). RESULTS: The overall number of patients analysed was 964. No relevant statistical difference was found among neonatal outcomes across the four ovarian response categories. Neonatal weight (in grams) was comparable between all groups (3222 ± 607 versus 3254 ± 537 versus 3235 ± 575 versus 3200 ± 622; P = 0.85, in categories 1, 2, 3 and 4, respectively). No statistically significant differences were found among the ovarian response categories for birth weight z-scores (taking into account neonatal sex and delivery term). The incidence of pre-term birth and low birth weight was comparable across the different ovarian response groups (P = 0.127 and P = 0.19, respectively). Finally, the occurrence of adverse obstetric outcomes did not differ among the ovarian response categories. Multivariate regression analysis revealed that the number of oocytes was not associated with neonatal birth weight. CONCLUSIONS: No association was found between ovarian response and adverse perinatal outcomes in antagonist IVF and intracytoplasmic sperm injection cycles. Future, larger scale and prospectively designed investigations are needed to validate these results.

Frozen-warmed blastocyst transfer after 6 or 7 days of progesterone administration: impact on live birth rate in hormone replacement therapy cycles.

OBJECTIVE: To study the difference in live birth rate (LBR) between frozen-warmed blastocyst transfer (FET) on the 6th or the 7th day of progesterone administration in artificially prepared cycles. DESIGN: Retrospective cohort study. SETTING: Tertiary university-based referral hospital. PATIENT(S): Patients who underwent FET between December 2015 and December 2017 in a hormone replacement therapy cycle (HRT). INTERVENTION(S): Group A included all eligible patients who underwent transfer of a vitrified-warmed blastocyst on the 6th day of progesterone administration; group B included patients who underwent blastocyst transfer on the 7th day of progesterone. The artificial HRT protocol in this study consisted of estrogen administration at a dose of 2 mg twice daily for 7 days followed by 2 mg three times daily for 6 days and micronized vaginal progesterone 200 mg three times daily from an adequately considered endometrial thickness onward. MAIN OUTCOME MEASURE(S): Live birth rate. RESULTS: The study included 619 patients, 346 in group A and 273 in group B. The LBRs were comparable between both groups (36.6% for group A and group B), even after adjustment for confounding factors (adjusted odds ratio 1.073, 95% confidence interval 0.740-1.556). Subgroup analysis revealed significantly higher miscarriage rates for day 6 blastocysts transferred on the 6th day of progesterone supplementation compared with transfer on the 7th day of progesterone supplementation (50.0% versus 21.4%, respectively). Additionally, there was a tendency toward a higher LBR when the 7-day progesterone supplementation protocol was used for transfer of a day 6 blastocyst (21.5% and 35.5% for group A and group B, respectively). CONCLUSION: Warmed blastocyst transfer on the 6th compared with the 7th day of progesterone administration in an HRT cycle results in similar LBR. Subgroup analysis of day 6 blastocysts showed significantly higher miscarriage rates when FET was performed on the 6th day of progesterone administration.

Impact of Serum Estradiol Levels Prior to Progesterone Administration in Artificially Prepared Frozen Embryo Transfer Cycles.

Background: The need for endocrine monitoring in artificial cycles for frozen embryo transfer (FET) remains unclear and, more specifically, the value of the late-proliferative phase serum estradiol (E2) levels is with conflicting evidence in current literature. Objective: To investigate whether artificial FET cycles require endocrine monitoring for the serum E2 level prior to initiation of exogenous progesterone administration after an endometrial thickness of 6.5 mm has been reached. Design: One thousand two hundred and twenty-two (n = 1,222) artificial FETs performed in a tertiary center between 2010 and 2015 were subdivided into 3 groups according to the following late-proliferative serum E2 level percentiles: ≤p10 (E2 ≤144 pg/ml; n = 124), p11-p90 (E2 from 145 to 438 pg/ml; n = 977) and >p90 (E2 >439 pg/ml; n = 121). A mixed-effects multilevel multivariable regression analysis was performed to assess the potential effect of the late-proliferative E2 level on the live birth rate (LBR). Results: The level of late-proliferative circulating E2 showed no significant difference in terms of LBR after FET. Specifically, the multivariable regression model demonstrated a LBR of 19.5% for the p11-p90 reference group, compared to 24.4% for the ≤p10 (p = 0.251) and 19.5% for the >p90 group (p = 0.989). Conclusion: In this large retrospective dataset, no association was observed between late-proliferative phase serum E2 levels and LBR following FET in artificially prepared cycles. Although, caution is warranted due to the retrospective nature of the analysis and the potential for unmeasured confounding, we argue that monitoring of the late-proliferative serum E2 levels and using them to guide clinical decision-making (e.g., medication step-up, cycle prolongation or cancelation) may be of questionable value.

Heterogeneity Among Poor Ovarian Responders According to Bologna Criteria Results in Diverging Cumulative Live Birth Rates.

Research Question: Does reproductive outcome differ among the various subgroups of poor ovarian responders according to the Bologna criteria? Design: This was a retrospective, cohort study including poor ovarian responders according to Bologna criteria, undergoing an ICSI cycle from January 2011 until December 2017. Patients were divided into four groups: (1) age ≥ 40 years and abnormal ovarian response test, (2) age ≥ 40 years, abnormal ovarian reserve test and one previous poor response to stimulation, (3) age ≥ 40 years and one previous poor response, (4) abnormal ovarian reserve test and one previous poor response. Result(s): Overall, 846 cycles in 706 Bologna poor ovarian responders were included: 310 cycles in group 1, 169 in group 2, 52 in group 3, and 315 in group 4. There were significant differences in age, antral follicle count, antimüllerian hormone, cycle cancellation rates, and number of retrieved oocytes between the four groups. Live birth and cumulative live birth rate differed significantly between groups and were highest in Group 4 [Live birth rate: 7.4% (1) vs. 4.1% (2) vs. 5.8% (3) vs. 13.4% (4), p = 0.001 and Cumulative live birth rate: 8.3% (1) vs. 4.1 % (2) vs. 9.6% (3) vs. 16.8% (4) p < 0.001]. The multivariate GEE analysis revealed that the number of MIIs and the Bologna criteria pattern were the variables which were significantly associated with cumulative live birth rate. Conclusion(s): Poor ovarian responders represent a heterogeneous population. The young subpopulation has a better clinical prognosis in terms of fresh and cumulative live birth rate.

Current Therapeutic Options for Controlled Ovarian Stimulation in Assisted Reproductive Technology.

Assisted reproduction technologies have substantially advanced since the birth of the first in vitro fertilization baby, and innovations within in vitro fertilization laboratories have been of paramount importance for the overall assisted reproduction technology success rates. However, one of the milestones in the history of in vitro fertilization is irrefutably the introduction of conventional ovarian stimulation. The objective of the present review is to provide an update on conventional ovarian stimulation, by giving an overview of treatment milestones, together with the latest innovations currently being investigated. The realization of an assisted reproduction technology treatment depends on many steps that can be medically manipulated and must be harmoniously combined, starting from the follicular phase and ending with luteal phase support. New technologies in the pharmaceutical sector are fundamental to optimize efficiency and tailor treatment approaches to individual needs. The present review aims to offer physicians a useful summary of the more recent publications and to facilitate the translation of research findings into daily clinical practice.